Increasing evidence suggests that transient ischemia to the heart, brain and kidney may lead to myocardial infarction, stroke and acute tubular necrosis by producing swelling of endothelial and interstitial cells. The increase in volume of these cells appears to partially occlue the capillary lumina, leading to further tissue ischemia, and finally necrosis. If this view is correct, myocardial infarction, stroke and acute tubular necrosis reduce to cellular diseases of volume regulation. The aim of the proposed research is to examine the nature and composition of the intracellular fluids, and their relationship to transport of salt and water across cell membranes and across epithelia. Specifically, the degree and significance of intracellular compartmentalization and binding within muscle and epithelia will be studied and related to the chemical composition of these cells. The kinetics of uptake and extrusion of sodium will be examined and related both to the nature and composition of the intracellular fluids and to active transport of sodium. Active transport will be characterized both electrophysiologically and metabolically. Finally, the physiology of the apical "tight" junctions will be studied and related to transport across epithelial membranes. This project will bring a wide spectrum of experimental techniques to bear on the central problem, including: ion-sensitive microelectrodes, classical electrophysiologic techniques, nuclear magnetic resonance, electron microscopy, nuclear microdissection, electron probe microanalysis and chemical and radioactive tracer analysis of tissue.